Systemic Dissemination of Clostridium difficile Toxins A and B Is Associated With Severe, Fatal Disease in Animal Models

• Published in: The Journal of infectious diseases 2012-02, Vol.205 (3), p.384-391
• Main Authors: Steele, Jennifer, Chen, Kevin, Sun, Xingmin, Zhang, Yongrong, Wang, Haiying, Tzipori, Saul, Feng, Hanping
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - immunology; Antitoxins - administration & dosage; Antitoxins - immunology; Ascites; Bacteremia; BACTERIA; Bacterial Proteins - analysis; Bacterial Proteins - blood; Bacterial Proteins - toxicity; Bacterial Toxins - analysis; Bacterial Toxins - blood; Bacterial Toxins - toxicity; Bacteriology; Biological and medical sciences; Body fluids; Body Fluids - chemistry; Cell Survival - drug effects; Clostridium difficile; Clostridium difficile - pathogenicity; Clostridium Infections - complications; Clostridium Infections - mortality; Cytokines; Cytokines - blood; Cytological Techniques - methods; Disease manifestations; Disease models; Disease Models, Animal; Enterotoxins - analysis; Enterotoxins - blood; Enterotoxins - toxicity; Fundamental and applied biological sciences. Psychology; Infections; Infectious diseases; Major and Brief Reports; Medical sciences; Mice; Mice, Inbred C57BL; Microbiology; Miscellaneous; Swine; Toxemia - mortality; Toxins
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jir748

Background. Clostridium difficile infection (CDI) can cause a wide range of disease, from mild diarrhea to fulminant systemic disease. The incidence of systemic CDI with fatal consequence has increased rapidly in recent years. Methods. Using an ultrasensitive cytotoxicity assay, we measured C. difficile toxin A (TcdA) and C. difficile toxin B (TcdB) in sera and body fluids of piglets and mice exposed to C. difficile to investigate the relationship between the presence of toxins in body fluids and systemic manifestations of CDI. Results. We found that both TcdA and TcdB disseminate systemically, with toxins present in the sera and body fluids of infected animals, and toxemia is significantly correlated with the development of systemic CDI. The systemic administration of neutralizing antibodies against both toxins blocked the development of systemic disease in mice. We measured cytokine concentrations in the sera of mice and piglets with systemic and nonsystemic CDI and found that proinflammatory mediators were considerably elevated in animals with systemic CDI. Conclusion. Our study demonstrates the existence of a strong correlation between toxemia and the occurrence of systemic disease, supporting the hypothesis that systemic CDI is most likely due to the toxicity of TcdA and TcdB and the induction of proinflammatory cytokines by the toxins.